Abstract

Background

Chemotherapy in cancer patients can be associated with serious short- and long-term
adverse neurological effects, such as leukoencephalopathy and cognitive impairment,
even when therapy is delivered systemically. The underlying cellular basis for these
adverse effects is poorly understood.

Results

We found that three mainstream chemotherapeutic agents – carmustine (BCNU), cisplatin,
and cytosine arabinoside (cytarabine), representing two DNA cross-linking agents and
an antimetabolite, respectively – applied at clinically relevant exposure levels to
cultured cells are more toxic for the progenitor cells of the CNS and for nondividing
oligodendrocytes than they are for multiple cancer cell lines. Enhancement of cell
death and suppression of cell division were seen in vitro and in vivo. When administered systemically in mice, these chemotherapeutic agents were associated
with increased cell death and decreased cell division in the subventricular zone,
in the dentate gyrus of the hippocampus and in the corpus callosum of the CNS. In
some cases, cell division was reduced, and cell death increased, for weeks after drug
administration ended.

Conclusion

Identifying neural populations at risk during any cancer treatment is of great importance
in developing means of reducing neurotoxicity and preserving quality of life in long-term
survivors. Thus, as well as providing possible explanations for the adverse neurological
effects of systemic chemotherapy, the strong correlations between our in vitro and in vivo analyses indicate that the same approaches we used to identify the reported toxicities
can also provide rapid in vitro screens for analyzing new therapies and discovering means of achieving selective protection
or targeted killing.